Abstract P330: Nogo-B Regulates Vascular Sphingolipids To Impact Hepatic Gluconeogenesis And Blood Pressure

Worldwide >1.6 billion of people are overweight or obese, a condition causally linked to type 2 diabetes (T2D), metabolic syndrome, cardiovascular diseases. In addition to precede the onset of diabetic CV complications, growing evidence implicate endothelial dysfunction to contribute to metabolic disorders. The sphingolipid ceramides, important membrane components and intracellular signaling molecules, have been implicated in insulin resistance and diabetes, and its vascular complications. However, mechanisms disrupting sphingolipid homeostasis and its impact on vascular and metabolic dysfunctions remain poorly understood. Recently, we discovered that Nogo-B, a membrane protein of the endoplasmic reticulum, inhibits sphingolipid de novo biosynthesis via serine palmitoyltransferase, first and rate liming enzyme, to impact vascular functions. Thus, the aim of this study was to investigate how Nogo-B regulation of sphingolipid signaling in the endothelium impacts metabolic and vascular homeostasis in obesity-T2D model.We discovered that in diabetic resistance arteries Nogo-B was overexpressed and correlated with a marked decrease of ceramides and sphingomyelins, vascular dysfunction, and hypertension. Interestingly, systemic, and endothelial genetic deletion of Nogo-B protected the mice from vascular dysfunctions and hypertension in diabetes, by preserving local sphingolipid metabolism and signaling. These findings, the first to investigate local mechanisms of sphingolipid metabolism derangement and its pathological implications, are a paradigm shift for the long-standing belief that vascular ceramide accrual underlies diabetic dysfunctions. Furthermore, our data also show that S1P secreted by the endothelium can downregulate hepatic gluconeogenesis, and that Nogo-B-mediated suppression of sphingolipid de novo biosynthesis can remove S1P brake on liver glucose production and exacerbates diabetes. Our findings suggest that suppression of endothelial sphingolipid signaling via Nogo-B underlies both vascular and metabolic dysfunctions in diabetes.